Orphanet Journal of Rare Diseases BioMed Central

Review Open Access Congenital Cataracts – Facial Dysmorphism – Neuropathy Luba Kalaydjieva*

Address: Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Hospital Avenue, WA 6009 Nedlands, Australia Email: Luba Kalaydjieva* - [email protected] * Corresponding author

Published: 29 August 2006 Received: 11 July 2006 Accepted: 29 August 2006 Orphanet Journal of Rare Diseases 2006, 1:32 doi:10.1186/1750-1172-1-32 This article is available from: http://www.OJRD.com/content/1/1/32 © 2006 Kalaydjieva; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex developmental disorder of autosomal recessive inheritance. To date, CCFDN has been found to occur exclusively in patients of Roma (Gypsy) ethnicity; over 100 patients have been diagnosed. Developmental abnormalities include congenital cataracts and microcorneae, primary hypomyelination of the peripheral nervous system, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism and hypogonadism. Para-infectious rhabdomyolysis is a serious complication reported in an increasing number of patients. During general anaesthesia, patients with CCFDN require careful monitoring as they have an elevated risk of complications. CCFDN is a genetically homogeneous condition in which all patients are homozygous for the same ancestral mutation in the CTDP1 gene. Diagnosis is clinical and is supported by electrophysiological and brain imaging studies. The major differential diagnosis is Marinesco-Sjögren syndrome. The definitive diagnosis is molecular, based on homozygosity for the CTDP1 mutation. CTDP1 maps to 18qter and encodes a protein phosphatase whose only known substrate is the phosphorylated serine residues of the carboxy-terminal domain of the largest subunit of RNA polymerase II, indicating that CCFDN affects basic cellular processes of gene expression and developmental regulation. Families benefit from genetic counselling and predictive testing. Management includes surgical treatment of the cataracts, and rehabilitation and corrective orthopaedic surgery for the peripheral neuropathy. Thus, the most disabling manifestations, though not curable, are manageable, and allow an acceptable quality of life and everyday living. Current data indicate that patients survive well into adulthood.

Disease name Primary diagnostic criteria Congenital Cataracts Facial Dysmorphism Neuropathy • Bilateral congenital cataracts, microcornea, microph- (CCFDN) syndrome thalmos, micropupils

Definition/diagnostic criteria • Developmental delay CCFDN is a complex developmental disorder of auto- somal recessive inheritance which, so far, has been found • Small stature and low weight to occur exclusively in patients of Roma (Gypsy) ethnicity [1,2]. • Hypo/demyelinating neuropathy

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• Mild facial dysmorphism morphism develops in late childhood and is more evident in male than in female subjects. It includes a prominent • Mild hypogonadism midface with a well developed nose, thickening of the perioral tissues, forwardly directed anterior dentition and Additional criteria hypognathism. Skeletal deformities are present in most • Mild cognitive deficit patients, especially adults. Foot deformities, namely pes cavus or pes equinovarus with clawing of the toes, are very • Cerebral and spinal cord atrophy on neuroimaging common. Claw hand deformity develops in the course of the disease and is observed in most adult patients. Kypho- • Post-infectious rhabdomyolysis scoliosis may develop and leads to reduced vital capacity.

• Osteoporosis The most striking neurological manifestation is a symmet- ric, distally accentuated, predominantly motor peripheral Epidemiology neuropathy. Motor involvement is evident in all affected The CCFDN mutation is particularly common among the subjects, including young children, and progresses to Rudari, an endogamous, recently founded Roma popula- severe disability in the third decade. Loss or depression of tion, in whom the carrier rate is around 6–7% [3,4]. In tendon reflexes, initially in the lower limbs, is universally other Gypsy groups, it is ~1%. The disorder has so far been observed. Nerve conduction velocity is normal in early diagnosed in over 100 Roma patients, whose countries of infancy and declines after age 18 months, stabilizing at residence reflect past and recent migrations of the affected ~20 m/s after 4 years [8]. Distal motor latency is increased. population, as well as access to healthcare and awareness Sensory action potential values are of normal amplitude, of this syndrome among health care providers. Most suggesting a relatively uniform degree of slowing of con- known affected subjects belong to the traditional Roma duction across nerve fibres, consistent with congenital population of Balkan and Central European countries hypomyelination. Neuropathological evidence of primary (Bulgaria, Romania, Serbia, Greece, Hungary, the Czech hypomyelination is provided by nerve biopsy studies, Republic), or are recent migrants to Austria and Germany; showing also a superimposed demyelination/remyelina- with cases also diagnosed in Italy, France, The Nether- tion and axonal degeneration increasing with age. lands, USA and Canada. CCFDN should be considered as the most likely diagnosis in infants of Roma ethnicity pre- Other, less consistent, neurological abnormalities include senting with congenital cataracts. bilaterally extensor plantar responses, choreiform move- ments, mild ataxia and upper limb postural tremor. Clinical description Abnormal electroencephalographic recordings are a very The CCFDN phenotype is complex and affects multiple common finding, with usually diffuse slow wave activity. organs and tissues, mostly during intra-uterine develop- Brain and spinal cord abnormalities have been identified ment. Detailed descriptions of the clinical manifestations in many patients by magnetic resonance imaging (MRI) are available [2,5-7]. examination [2]. The changes appear to be age-related and may not be detectable in affected children. The abnormal- Prenatal eye development is invariably affected and the ities include diffuse cerebral atrophy with enlargement of congenital cataracts are the first CCFDN manifestation, the lateral ventricles, and spinal cord atrophy sometimes recognisable in early infancy. The cataracts are bilateral also involving the medulla oblongata. A recent study, and are characterised by anterior or posterior cortical using diffusion tensor MRI in a small group of CCFDN dense opacities with clouding of the adjacent part of the patients revealed a higher apparent diffusion coefficient lens nucleus or total cataracts involving the whole lens. and lower fractional anisotropy in the vermis and medulla These are accompanied by microcornea, microphthalmos oblongata, suggesting axonal loss in these parts of the and micropupils. Additional ophthalmological features brain [8]. Mild non-progressive cognitive deficit is often include floppy eyelids and long and dense eyelashes, nys- present; however, its assessment should take into account tagmus and strabismus [7]. the visual impairment, as well as possible social depriva- tion of the affected subjects. Early motor, as well as intellectual, development is delayed, with most patients starting to walk between 2 Severe myalgia, weakness and massive myoglobinuria, and 3 years and to talk after 3 years of age. presumably following unspecified viral infections, are reported in an increasing number of patients. Para-infec- On physical examination, all patients are of small stature tious rhabdomyolysis, which is rare in the general popu- and most are also of low weight. Head circumference is lation [9], may be a common environmentally-triggered reduced; however, its ratio to height is normal. Facial dys- feature of the CCFDN syndrome, possibly related to an

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inability of the transcription machinery to meet the higher Diagnostic methods demands imposed by the febrile condition. Patients and The clinical diagnosis is based on observation of the care-providers should be aware of this complication and symptoms and manifestations described above, sup- seek prompt medical attention to prevent acute kidney ported by electrophysiological and brain imaging studies. failure. The definitive diagnosis is molecular, based on homozy- gosity for the splicing mutation in intron 6 of the CTDP1 Sex hormone (testosterone and oestrogen) levels are gene. The test is a polymerase chain reaction (PCR)-based decreased. External secondary sexual characteristics restriction fragment length polymorphism (RFLP) assay, appear normal; however most adult female patients have relying on the abolition of an NlaIII restriction site by the irregular menstrual cycles progressing to secondary amen- mutation [3]. Molecular testing based on linkage analysis orrhea at age 25–35 years. Bone mineral density is may be problematic, due to the recent origin of the muta- reduced both in compact and trabecular bone. tion on a common haplotype background and the persist- ing presence of the ancestral haplotype on normal Aetiology chromosomes in the same population [3]. CCFDN is a genetically homogeneous condition, where all patients are homozygous for the same ancestral muta- So far, CCFDN is known to affect patients of Roma tion. The CCFDN gene maps to 18qter [1]. The recently (Gypsy) ethnicity, with the history of this population identified mutation is a C>T substitution 389 bp down- helping to identify the molecular basis of the disease. It is stream of the exon 6/intron 6 junction of the Carboxy-Ter- logical to expect that there are affected individuals of dif- minal Domain Phosphatase 1 (CTDP1) gene [3]. The ferent ethnicity displaying similar phenotypic features mutation occurs in an antisense Alu element and triggers and that these patients would have other mutations of the a rare mechanism of aberrant splicing: it creates a perfect same gene. In such cases, sequencing analysis of CTDP1, donor splice site which, in turn, activates an upstream as well as of the SIL1 gene recently found to be mutated in cryptic acceptor site, leading to the insertion of 95 nucle- Marinesco-Sjögren syndrome (MSS) [12,13], will not only otides of the intronic Alu sequence into the processed help the diagnostic investigations in the specific affected CTDP1 transcript. The insertion causes a shift in the read- families, but will also contribute to understanding the ing frame and a premature termination codon. Since both molecular pathogenesis of the two disorders. It is advisa- normal and aberrant splicing occur in CCFDN cells [3], ble to make cultured cells (skin fibroblasts, lymphoblast- the mutation is predicted to lead to partial protein defi- oid cells, myoblasts, or Schwann cells) available for ciency. The CTDP1 gene encodes a protein phosphatase, molecular studies, since the mutation(s) can be predicted commonly referred to as FCP1, whose only known sub- to cause partial deficiency, and are thus likely to occur in strate is the phosphorylated serine residues of the carboxy- introns and regulatory sequences and to require RNA- terminal domain (CTD) of the largest subunit of RNA based analysis for elucidation. polymerase II [10]. RNA polymerase II is responsible for the transcription of protein-encoding genes in eukaryotic Differential diagnosis cells, and the level of CTD phosphorylation is considered In early infancy, when most features of the CCFDN syn- to be a key mechanism for the regulation of gene expres- drome have yet to appear, a differential diagnosis to be sion [11]. In addition to, and independent of its enzyme considered is galactokinase deficiency, an inborn error of activity, FCP1 has been proposed to play other roles in metabolism common among the Roma which, if transcription: as a positive transcription regulator, an untreated, leads to the development of cataracts in the elongation factor, a factor counteracting the Srb-10 com- first weeks of life [14,15]. The two conditions can be dis- plex (which down-regulates the expression of cell cycle tinguished by specialised ophthalmological examination, and developmentally regulated genes), and in the mecha- searching for the additional ocular manifestations of nisms of splicing. At this stage, it is unclear which molec- CCFDN (described above), as well as by testing for the ular function(s) is most affected by the CCFDN mutation two founder mutations – in the CTDP1 and GALK1 genes. and thus responsible for the disease phenotype. The major differential diagnosis is MSS [12,13,16,17], Regardless of the need for understanding the specific whose phenotypic features partly overlap those of CCFDN molecular pathogenesis, it is already clear that CCFDN [6,8] (Table 1). While substantial clinical heterogeneity affects basic cellular mechanisms of gene expression and exists among patients diagnostically labelled as MSS, their developmental regulation. The disorder belongs to mutations in the SIL1 gene on chromosome 5q seem to the (currently) small group of "transcription syndromes" result in a relatively homogeneous phenotype, character- and, at present, is the only known defect directly involving ised by congenital cataracts, developmental delay, severe RNA polymerase II-mediated gene expression. ataxia and cerebellar atrophy, and chronic myopathy [12,13]. The heterogeneity is still incompletely resolved,

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Table 1: Clinical criteria in differential diagnosis of Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) and Marinesco- Sjögren syndrome (MSS)

SYMPTOMS CCFDN MSS

Microcornea, microphthalmos, micropupils Yes No Developmental delay Yes Yes Small stature Yes Yes Facial dysmorphism Yes, mild, late childhood No Peripheral neuropathy Yes, hypomyelinating Rare, variable type Ataxia Rare, mild* Severe cerebellar Brain MRI Cerebral atrophy* Cerebellar atrophy Myopathy Acute para-infectious rhabdomyolysis* Chronic Cognitive deficit Mild* Variable degree Hypogonadism Mild* Variable in degree and origin (hypo/hypergonadotrophic)

* Manifestations whose frequency and nature require further characterisation.

with some "typical", as well as "atypical" MSS cases failing 40 years of age). While the most disabling manifestations to show linkage to 5q and/or mutations in SIL1 [13,18]. involving the eyes and the peripheral nervous system are not curable, they are manageable, allowing an acceptable Genetic counselling quality of life and performance of daily activities. The disorder is autosomal recessive, with a Mendelian risk of 25% for subsequent pregnancies. Given the high fre- Unresolved questions quency of the mutation, and the endogamous tradition of Clinical features the affected population, discussions of consanguinity are The nature of the pathological changes in the central nerv- irrelevant and can be counterproductive. Most affected ous system is still to be resolved. At present, it is unclear families are very receptive to genetic counselling and pre- whether the brain and spinal cord atrophy observed on dictive testing. MRI result from primary hypomyelination, as is the case for the peripheral nervous system [2,5] or secondary Prenatal diagnosis degenerative processes. Furthermore, the recently Prenatal analysis is best performed by testing for the dis- reported diffusion tensor MRI evidence of axonal loss in ease mutation on DNA extracted from chorionic villus the brain [8] needs to be confirmed in larger groups of samples. patients. The nature of the endocrine abnormalities is also poorly defined. Although the hypogonadism seen in Management CCFDN patients has been classified as hypogonado- Management includes the treatment of cataracts, and trophic [2], the evidence is not conclusive, and the prob- rehabilitation and corrective surgery for the peripheral lem may in fact reside in changes in the expression profile neuropathy. Eye surgery may be complicated by strong of the gonads. The frequency of rhabdomyolysis in postoperative inflammatory reactions, as well as a strong CCFDN patients and the nature of the factors triggering unspecific foreign-body reaction to contact lenses and this severe complication remain to be determined; careful intra-ocular lenses, with a generally better tolerance to collection of case histories and patient follow-up will pro- intra-ocular lenses [7]. CCFDN patients are prone to vide this information. developing severe and potentially life-threatening compli- cations during anaesthesia, such as pulmonary oedema, Molecular mechanisms inspiratory stridor, malignant hyperthermia and epileptic Further studies are needed to elucidate the specific molec- seizures [6,7] and thus need close monitoring and possi- ular processes that lead to the phenotypic manifestations bly intensive post-operative care. of CCFDN. The mutated protein is believed to be of uni- versal importance for the regulation of RNA polymerase II Prognosis activity and the CCFDN mutation is expressed in all cell The recent recognition of CCFDN as a novel disease types investigated, yet the clinical phenotype is limited to entity, and the lack of prospective follow-up does not just a few of them. This cell specificity, possibly resulting allow an evidence-based prognosis regarding life expect- from differences in back-up mechanisms and in the rela- ancy. Current observations indicate that patients survive tive contribution of other CTD phosphatases to RNA well into adulthood (the oldest known cases being over polymerase II regulation, is a major question, resolution

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Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach- Faller N, Rudnik-Schoneborn S, Blaschek A, Wolf NI, Harting I, North Sir Paul Nurse, Cancer Research UK K, Smith J, Muntoni F, Brockington M, Quijano-Roy S, Renault F, Her- Your research papers will be: rmann R, Hendershot LM, Schroder JM, Lochmuller H, Topaloglu H, Voit T, Weis J, Ebinger F, Zerres K: Mutations in SIL1 cause Mari- available free of charge to the entire biomedical community nesco-Sjogren syndrome, a cerebellar ataxia with cataract peer reviewed and published immediately upon acceptance and myopathy. Nature Genet 2005, 37:1312-1314. 14. Kalaydjieva L, Perez-Lezaun A, Angelicheva D, Onengut S, Dye D, cited in PubMed and archived on PubMed Central Bosshard N, Jordanova A, Savov A, Yanakiev P, Kremensky I, Radeva yours — you keep the copyright B, Hallmayer J, Markov A, Nedkova V, Tournev I, Aneva L, Gitzelmann R: A founder mutation in the GK1 gene is responsible for Submit your manuscript here: BioMedcentral http://www.biomedcentral.com/info/publishing_adv.asp

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